Ketogenic Diet Therapy for Autism Spectrum Disorder

• ClinicalTrials.gov Identifier: NCT02477904
• Recruitment Status: Completed
• First Posted: June 23, 2015
• Last Update Posted: September 20, 2019
• Sponsor: Shriners Hospitals for Children
• Collaborator: University of Hawaii
• Information provided by (Responsible Party): Ryan Lee, MD, Shriners Hospitals for Children

Tracking Information

• First Submitted Date: June 16, 2015
• First Posted Date: June 23, 2015
• Last Update Posted Date: September 20, 2019
• Study Start Date: March 2015
• Actual Primary Completion Date: April 28, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 12, 2016)

Change from baseline in core symptoms of ASD [ Time Frame: Pre- and post-ketogenic diet intervention (at baseline, and after three and six months on the ketogenic diet) ]

Assess core autistic symptoms through review/analysis of responses to the following measurement instruments: Autism Diagnostic Observation Schedule - Second Edition (ADOS-2); Asperger Syndrome Diagnostic Scale (ASDS); Childhood Autism Rating Scale (CARS-2); Gilliam Autism Rating Scale (GARS-3); Social Responsiveness Scale - Second Edition (SRS-2); Diagnostic and Statistical Manual IV Text Revision (DSM-IV-TR) and DSM-V ASD criteria; standardized intelligence tests (if available, administered by child's school); and Vanderbilt ADHD Diagnostic Teacher Rating Scale Forms (Vanderbilt).

Original Primary Outcome Measures (submitted: June 22, 2015)

Change from baseline in core symptoms of ASD [ Time Frame: Pre- and post-ketogenic diet intervention (at baseline, and after three and six months on the ketogenic diet) ]

Assess core autistic symptoms through review/analysis of responses to the following measurement instruments: Asperger Syndrome Diagnostic Scale (ASDS), Childhood Autism Rating Scale (CARS-2), Gilliam Autism Rating Scale (GARS-3), Social Responsiveness Scale - Second Edition (SRS-2), standardized intelligence tests (if available, administered by child's school), and Vanderbilt ADHD Diagnostic Teacher Rating Scale Forms (Vanderbilt).

Current Secondary Outcome Measures (submitted: June 22, 2015)

• Change from baseline in the number of medications used for ASD management [ Time Frame: Pre- and post-ketogenic diet intervention (at baseline, and after three and six months on the ketogenic diet) ]
  Assess changes through the review/analysis of self-report and medical record data.
• Change from baseline in the dosage of medications used for ASD management [ Time Frame: Pre- and post-ketogenic diet intervention (at baseline, and after three and six months on the ketogenic diet) ]
  Assess changes through the review/analysis of self-report and medical record data.
• Change from baseline in the number of lab tests ordered for ASD management [ Time Frame: Pre- and post-ketogenic diet intervention (at baseline, and after three and six months on the ketogenic diet) ]
  Assess changes through the review/analysis of self-report and medical record data.
• Change from baseline in the number of emergency room or hospital visits for ASD management [ Time Frame: Pre- and post-ketogenic diet intervention (at baseline, and after three and six months on the ketogenic diet) ]
  Assess changes through review/analysis of self-report and medical record data.
• Change from baseline in subject/family satisfaction with the ketogenic diet [ Time Frame: Pre- and post-ketogenic diet intervention (at baseline, and after three and six months on the ketogenic diet) ]
  Assess changes in subject/family satisfaction with the ketogenic diet through review/analysis of responses to a questionnaire.
• Change from baseline in biochemical profiles due to the ketogenic diet [ Time Frame: Pre- and post-ketogenic diet intervention (at baseline, and after three and six months on the ketogenic diet) ]
  Assess biochemical profile differences and changes through the analysis of serum and urine ketone levels
• Change from baseline in biochemical profiles due to the ketogenic diet [ Time Frame: Pre- and post-ketogenic diet intervention (at baseline, and after three and six months on the ketogenic diet) ]
  Assess biochemical profile differences and changes through the analysis of blood and stool (gut microbiome) specimen samples

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: April 12, 2016)

Possible effects of the ketogenic diet [ Time Frame: Post-ketogenic diet intervention ]

Participants on the ketogenic diet will be followed clinically with standard of care until they are 21 years of age to examine the long-term benefits or risks of the KD.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Ketogenic Diet Therapy for Autism Spectrum Disorder
• Official Title: Ketogenic Diet Therapy for Autism Spectrum Disorder
• Brief Summary: This study will assess the effectiveness of the ketogenic diet (high-fat, low-carbohydrate, and moderate protein) in treating autism spectrum disorder (ASD). Three study groups will be comprised of children (2-21 years of age) based on whether or not they have ASD and receive the ketogenic diet - ASD/ketogenic diet, ASD/non-ketogenic diet, and non-ASD/non-ketogenic diet.

Detailed Description

Recent studies have shown that the ketogenic diet (high-fat, low-carbohydrate, and moderate protein; induce a shift from the primary metabolism of glucose to ketones) or Modified-Atkins diet may be effective in treating autism. Research on the Black and Tan BRachyury (BTBR) T+tf/J mouse strain, characterized by an autism-like behavioral phenotype, has demonstrated the efficacy of a ketogenic diet in improving autism. Although, modified diets, such as the Feingold diet, low-sugar diet, or gluten-free diet, have shown behavioral improvements in patients with Attention Deficit Hyperactivity Disorder (ADHD), the ketogenic diet has not been studied in autism spectrum disorder (ASD) despite the high incidence of ADHD comorbidity. The findings from only one prospective, pilot study have been published, which reported significant behavioral improvement in all 18 autistic subjects after six months (assessed at intervals of four weeks on the diet and two weeks diet-free) on the ketogenic diet. Clearly, the ketogenic and other modified diets as promising treatments for ASD have been understudied. Additional clinical research is necessary to establish the ketogenic diet as a safe, effective treatment alternative for children with ASD.

This proposed research project will involve an ethnically diverse sample (varied genetic background and environmental exposure) to assess the efficacy of the ketogenic diet as a therapeutic intervention, and to understand its beneficial effects in children with ASD. The investigators anticipate that noteworthy findings will contribute to the sparse literature on ASD and effective dietary interventions and prompt future research collaborations with investigators from other medical centers and/or academic institutions. Funding for future research appears promising considering that ketogenic therapies are also a novel method for the treatment of a variety of disorders, including other neurodevelopmental disorders, diabetes, migraine headaches, brain tumors, multiple sclerosis, and obesity.

In addition, the investigators propose to also examine the potential changes in blood composition and intestinal (gut) microbiome in children with (without) ASD who are treated (not treated) with the ketogenic diet in light of the effect on their ASD symptomatology. The relationship between the gastrointestinal tract and the central nervous system has garnered increasing interest in the research community. The gut-brain interface describes a bidirectional relationship in which the central nervous system influences the gut and vice versa. Little is known about the mechanisms behind anecdotal reports of dietary success in humans, but it is suspected that alterations in gut microflora are involved. Mulle et al. (2013) postulated that the connection between the gut microbiome and ASD may be either the direct cause or as indirect consequence of atypical patterns of feeding and nutrition. Similarly, diet patterns, including the ketogenic diet, impact nutrient availability and thus indirectly modulate the gut microbiome. Multiple studies have confirmed differences in levels of gut commensals and overall metabolite profiles in fecal and urinary samples from healthy children compared to children with ASD, potentially as a result of changes in the microbiome. In the maternal immune activation mouse model of ASD, Hsiao et al. (2013) reported that probiotic treatment with B. fragilis could correct behavioral abnormalities and metabolomics profile typified in ASD and ameliorate ASD-relevant GI barrier deficits in mice. Sandler et al. (2000) demonstrated that oral vancomycin treatment showed short-term improvements in children with regressive-onset autism, suggesting that alterations in gut bacteria profile, in this case with antibiotic therapy, may improve autistic behavior. Studies of the gut microbiome in children with ASD may elucidate the role of diet and the alterations in gastrointestinal microbes related to ASD. As a result of these data, novel treatments may be discovered.

The specific aims of this study are:

Aim 1. To evaluate the effect of the ketogenic diet on the core symptoms of autism. The following instruments will be used to measure core autistic symptoms: a) Autism Diagnostic Observation Schedule - Second Edition (ADOS-2); b) Asperger Syndrome Diagnostic Scale (ASDS); c) Childhood Autism Rating Scale (CARS-2); d) Gilliam Autism Rating Scale (GARS-3); e) Social Responsiveness Scale - Second Edition (SRS-2); f) Diagnostic and Statistical Manual IV Text Revision (DSM-IV-TR) and DSM-V ASD criteria; g) Standardized social & intelligence tests (if available, administered by child's school); and h) Vanderbilt ADHD Diagnostic Teacher Rating Scale Forms (Vanderbilt).

Hypothesis: Participants who have ASD/on the ketogenic diet will have significantly lessened core autistic symptoms than those that have ASD/not on the ketogenic diet, between baseline to three and six months after the dietary intervention is initiated.

Aim 2. In anticipation of significant changes in core autistic symptomatology, to examine the effects of the ketogenic diet on the (a) number and dosage of medications used for behavioral management, (b) number of lab tests ordered for behavioral management, (c) number of emergency room or hospital visits for behavioral management, and (d) subject/family satisfaction with the ketogenic diet.

Hypothesis: The number (and/or dosage) of medications, lab tests ordered, and emergency room or hospital visits for behavioral management will decrease, and participant/family satisfaction will be high for participants who have ASD/on the ketogenic diet than those who have ASD/not on the ketogenic diet, between baseline to three and six months after the dietary intervention is initiated.

Aim 3. To compare differences and/or changes in (a) biochemical profiles as defined from blood and stool (gut or fecal microbiome) specimen samples and (b) serum and urine ketone levels.

Hypothesis: Participants who have ASD/on the ketogenic diet will have notably different biochemical profiles and significantly higher serum/urine ketone levels than those who have ASD/not on the ketogenic diet and typically developing controls on a regular diet, between baseline to three and six months after the dietary intervention is initiated.

The investigators anticipate that the KD will be effective in treating ASD, and further an understanding of dietary patterns and gastrointestinal alterations in ASD. Noteworthy findings will contribute to the sparse literature on the association between dietary intervention and neurodevelopmental disorders, and assist with obtaining future funding for higher-level clinical trials involving collaborative research with other medical centers and academic institutions. These initiatives, the investigators believe, are necessary to establish the KD as a novel, safe alternative to effectively treat patients with ASD.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Autism Spectrum Disorder

Intervention

Other: Ketogenic Diet

Dietary

Other Names:

• Classic Ketogenic Diet
• Shriner's Ketogenic Diet
• Non-Ketogenic Diet

Study Arms

• Experimental: ASD/KD
  Children (2-21 years of age) diagnosed with autism spectrum disorder (ASD) will receive the ketogenic diet (KD) intervention.
  Intervention: Other: Ketogenic Diet
• Active Comparator: ASD/non-KD
  Children (2-21 years of age) diagnosed with autism spectrum disorder (ASD) will not receive the ketogenic diet (KD) intervention.
  Intervention: Other: Ketogenic Diet
• Active Comparator: non-ASD/non-KD
  Typically developing children (2-21 years of age) diagnosed as not having autism spectrum disorder (ASD) will not receive the ketogenic diet (KD) intervention.
  Intervention: Other: Ketogenic Diet

Publications *

• Stafstrom CE, Rho JM. The ketogenic diet as a treatment paradigm for diverse neurological disorders. Front Pharmacol. 2012 Apr 9;3:59. doi: 10.3389/fphar.2012.00059. eCollection 2012.
• Evangeliou A, Vlachonikolis I, Mihailidou H, Spilioti M, Skarpalezou A, Makaronas N, Prokopiou A, Christodoulou P, Liapi-Adamidou G, Helidonis E, Sbyrakis S, Smeitink J. Application of a ketogenic diet in children with autistic behavior: pilot study. J Child Neurol. 2003 Feb;18(2):113-8. doi: 10.1177/08830738030180020501.
• Mantis JG, Fritz CL, Marsh J, Heinrichs SC, Seyfried TN. Improvement in motor and exploratory behavior in Rett syndrome mice with restricted ketogenic and standard diets. Epilepsy Behav. 2009 Jun;15(2):133-41. doi: 10.1016/j.yebeh.2009.02.038. Epub 2009 Feb 26.
• Ruskin DN, Svedova J, Cote JL, Sandau U, Rho JM, Kawamura M Jr, Boison D, Masino SA. Ketogenic diet improves core symptoms of autism in BTBR mice. PLoS One. 2013 Jun 5;8(6):e65021. doi: 10.1371/journal.pone.0065021. Print 2013.
• Niederhofer H. Association of attention-deficit/hyperactivity disorder and celiac disease: a brief report. Prim Care Companion CNS Disord. 2011;13(3):PCC.10br01104. doi: 10.4088/PCC.10br01104.
• Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012 Oct;13(10):701-12. doi: 10.1038/nrn3346. Epub 2012 Sep 12.
• Harris SL, Handleman JS. Age and IQ at intake as predictors of placement for young children with autism: a four- to six-year follow-up. J Autism Dev Disord. 2000 Apr;30(2):137-42. doi: 10.1023/a:1005459606120.
• Mulle JG, Sharp WG, Cubells JF. The gut microbiome: a new frontier in autism research. Curr Psychiatry Rep. 2013 Feb;15(2):337. doi: 10.1007/s11920-012-0337-0.
• Wang Y, Kasper LH. The role of microbiome in central nervous system disorders. Brain Behav Immun. 2014 May;38:1-12. doi: 10.1016/j.bbi.2013.12.015. Epub 2013 Dec 25.
• Adams JB, Johansen LJ, Powell LD, Quig D, Rubin RA. Gastrointestinal flora and gastrointestinal status in children with autism--comparisons to typical children and correlation with autism severity. BMC Gastroenterol. 2011 Mar 16;11:22. doi: 10.1186/1471-230X-11-22.
• Kang DW, Park JG, Ilhan ZE, Wallstrom G, Labaer J, Adams JB, Krajmalnik-Brown R. Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS One. 2013 Jul 3;8(7):e68322. doi: 10.1371/journal.pone.0068322. Print 2013.
• Ming X, Stein TP, Barnes V, Rhodes N, Guo L. Metabolic perturbance in autism spectrum disorders: a metabolomics study. J Proteome Res. 2012 Dec 7;11(12):5856-62. doi: 10.1021/pr300910n. Epub 2012 Nov 9.
• Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT, Conlon MA. Elevated fecal short chain fatty acid and ammonia concentrations in children with autism spectrum disorder. Dig Dis Sci. 2012 Aug;57(8):2096-102. doi: 10.1007/s10620-012-2167-7. Epub 2012 Apr 26.
• Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT, Conlon MA. Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder. Mol Autism. 2013 Nov 4;4(1):42. doi: 10.1186/2040-2392-4-42.
• Williams BL, Hornig M, Parekh T, Lipkin WI. Application of novel PCR-based methods for detection, quantitation, and phylogenetic characterization of Sutterella species in intestinal biopsy samples from children with autism and gastrointestinal disturbances. mBio. 2012 Jan 10;3(1):e00261-11. doi: 10.1128/mBio.00261-11. Print 2012.
• Yap IK, Angley M, Veselkov KA, Holmes E, Lindon JC, Nicholson JK. Urinary metabolic phenotyping differentiates children with autism from their unaffected siblings and age-matched controls. J Proteome Res. 2010 Jun 4;9(6):2996-3004. doi: 10.1021/pr901188e.
• De Angelis M, Piccolo M, Vannini L, Siragusa S, De Giacomo A, Serrazzanetti DI, Cristofori F, Guerzoni ME, Gobbetti M, Francavilla R. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS One. 2013 Oct 9;8(10):e76993. doi: 10.1371/journal.pone.0076993. eCollection 2013.
• Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, Codelli JA, Chow J, Reisman SE, Petrosino JF, Patterson PH, Mazmanian SK. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013 Dec 19;155(7):1451-63. doi: 10.1016/j.cell.2013.11.024. Epub 2013 Dec 5.
• Sandler RH, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP, Vaisanen ML, Nelson MN, Wexler HM. Short-term benefit from oral vancomycin treatment of regressive-onset autism. J Child Neurol. 2000 Jul;15(7):429-35. doi: 10.1177/088307380001500701.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 19, 2017): 119
• Original Estimated Enrollment (submitted: June 22, 2015): 150
• Actual Study Completion Date: April 28, 2017
• Actual Primary Completion Date: April 28, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Ages 2-21 years.
• Primary diagnosis of autism spectrum disorder.
• Parent/legal guardian and child able to read or understand English, and able/willing to provide informed consent/assent.
• Females of childbearing potential must have a negative pregnancy test result and agree to use a medically acceptable method of contraception throughout the entire study period and for 30 days after the last dose of study drug - childbearing potential is defined a girls who are > Tanner stage 2 and urine pregnancy tests are acceptable.

Exclusion Criteria:

• Known cardiac disorder including arrhythmias or hypertension.
• BMI < 3rd%ile.
• Carnitine deficiency (primary).
• Carnitine palmitoyltransferase (CPT) I or II deficiency.
• Carnitine translocase deficiency.
• Beta-oxidation defects - medium-chain acyl dehydrogenase deficiency (MCAD), long-chain acyl dehydrogenase deficiency (LCAD), short-chain acyld dehydrogenase deficiency (SCAD), long-chain 3-hydroxyacyl-coenzyme A (CoA) deficiency, and medium-chain 3-hydroxyacyl-CoA deficiency.
• Pyruvate carboxylase deficiency.
• Porphyria.
• Inability to maintain adequate nutrition.
• Patient or caregiver non-compliance.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Years to 21 Years (Child, Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02477904
• Other Study ID Numbers: HON1403
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Ryan Lee, MD, Shriners Hospitals for Children
• Original Responsible Party: Same as current
• Current Study Sponsor: Shriners Hospitals for Children
• Original Study Sponsor: Same as current
• Collaborators: University of Hawaii

Investigators

• Principal Investigator: Ryan W Lee, MD; Shriners Hospitals for Children, Honolulu

• PRS Account: Shriners Hospitals for Children
• Verification Date: September 2019